This multidisciplinary proposal aims to provide mechanistic insight into how dietary polyphenols confer resilience to chronic disease, such as metabolic syndrome (MetS) and type-2 diabetes (T2D). Bacterial cell biology combined with meta-omics approaches will first be used to assess acute effects of polyphenols on microbial viability and metabolic activity while in parallel monitoring acute changes in intestinal epitheliu (IE). Murine gut organoids will then be used to differentiate effects of polyphenols and biotransformed/microbial metabolites on IE followed by gut inoculation studies in germ-free mice to further define cause-effect relationships influencing energy metabolism. Consumption of polyphenol-rich foods is associated with reduced risk of chronic disease, but mechanism(s) of systemic protection offered by polyphenols have remained elusive due to generally poor polyphenol absorption and uncertainty about their molecular targets. Polyphenols accumulate in the intestine where they can be biotransformed by gut microbiota into simpler phenolic compounds with higher bioavailability; however, the levels and bioactivities of circulating metabolites may not be sufficient to explain their pharmacological effects. We observed that grape polyphenols (GP) can alter gut microbiota ecology and reduce intestinal and systemic inflammation in a high fat diet (HFD)-fed mouse model of MetS/T2D in association with improved glucose metabolism. Compared to HFD-fed controls, C57BL/6J mice fed isocaloric HFD supplemented with GP had less systemic inflammation, weight gain, adiposity, and glucose intolerance while consuming an equivalent amount of food. Intestinal tissues of mice fed GP- supplemented HFD had: 1) lower levels of inflammatory mediators, 2) higher occludin expression indicating improved barrier integrity; 3) increased Fiaf expression indicating less fat deposition in peripheral tissues; and 4) higher proglucagon expression, a precursor of GLP-1 and GLP-2 proteins that promote insulin production/secretion and maintain gut barrier integrity, respectively. These observations correlated with a dramatic increase in Akkermansia muciniphila, a microbe inhabiting the mucus layer covering the IE. Increased abundance of A. muciniphila was observed after gastric bypass surgery and metformin treatment, underlining its importance in positive metabolic outcomes. These data suggest why dietary polyphenols provide resilience against MetS/T2D; however, because GP are metabolized by gut microbiota it remains to be determined whether intact polyphenols or biotransformed metabolites mediate the bloom in A. muciniphila and intestinal gene expression changes. We propose to: 1) Determine the acute response of the microbiota and IE to GP and assess whether GP or their biotransformed metabolites increase A. muciniphila growth and 2) Uncouple the effects of GP and biotransformed /microbial metabolites on the IE using ex vivo cultured murine gut organoids followed by gut inoculation studies in germ-free (GF) mice to test their inflammatory and metabolic response to polyphenol- exposed microbiota of conventional (CONV) obese mice.